MK-8507 / Merck (MSD) - LARVOL DELTA

Ulonivirine (MK-8507) in Participants With Mild or Moderate Hepatic Impairment (MK-8507-014) (clinicaltrials.gov) - P1 | N=22 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Sep 2025 ➔ Sep 2026 | Trial primary completion date: Sep 2025 ➔ Sep 2026

Trial completion date • Trial primary completion date • Hepatitis C • Hepatology • Liver Failure

Dose Ranging, Switch Study of Islatravir (ISL) and Ulonivirine (MK-8507) Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013] (clinicaltrials.gov) - P2 | N=161 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion • Human Immunodeficiency Virus • Infectious Disease • CD4

Dose Ranging, Switch Study of Islatravir (ISL) and Ulonivirine (MK-8507) Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013] (clinicaltrials.gov) - P2 | N=161 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Dec 2024 ➔ Mar 2025 | Trial primary completion date: Dec 2024 ➔ Mar 2025

Trial completion date • Trial primary completion date • Human Immunodeficiency Virus • Infectious Disease • CD4

A Study of MK-8507 and Islatravir (MK-8591) in Healthy Adult Participants (MK-8507-016) (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

Ulonivirine (MK-8507) in Participants With Mild or Moderate Hepatic Impairment (MK-8507-014) (clinicaltrials.gov) - P1 | N=22 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Apr 2025 ➔ Sep 2025 | Trial primary completion date: Apr 2025 ➔ Sep 2025

Trial completion date • Trial primary completion date • Hepatitis C • Hepatology • Liver Failure

Dose Ranging, Switch Study of Islatravir (ISL) and Ulonivirine (MK-8507) Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013] (clinicaltrials.gov) - P2 | N=161 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Phase classification: P2b ➔ P2 | Trial completion date: Dec 2023 ➔ Sep 2024 | Trial primary completion date: Dec 2023 ➔ Sep 2024

Phase classification • Trial completion date • Trial primary completion date • Human Immunodeficiency Virus • Infectious Disease • CD4

Ulonivirine (MK-8507) in Participants With Mild or Moderate Hepatic Impairment (MK-8507-014) (clinicaltrials.gov) - P1 | N=22 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Oct 2025 ➔ Apr 2025 | Trial primary completion date: Oct 2025 ➔ Apr 2025

Trial completion date • Trial primary completion date • Hepatitis C • Hepatology • Liver Failure

Ulonivirine (MK-8507) in Participants With Mild or Moderate Hepatic Impairment (MK-8507-014) (clinicaltrials.gov) - P1 | N=22 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Feb 2024 ➔ Oct 2025 | Trial primary completion date: Feb 2024 ➔ Oct 2025

Trial completion date • Trial primary completion date • Hepatitis C • Hepatology • Liver Failure

Dose Ranging, Switch Study of Islatravir (ISL) and Ulonivirine (MK-8507) Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013] (clinicaltrials.gov) - P2b | N=161 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Jun 2023 ➔ Dec 2023 | Trial primary completion date: Jun 2023 ➔ Dec 2023

Trial completion date • Trial primary completion date • Human Immunodeficiency Virus • Infectious Disease • CD4

MK-8507 in Participants With Mild or Moderate Hepatic Impairment (MK-8507-014) (clinicaltrials.gov) - P1 | N=22 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Jan 2023 ➔ Feb 2024 | Trial primary completion date: Jan 2023 ➔ Feb 2024

Trial completion date • Trial primary completion date • Hepatitis C • Hepatology • Liver Failure

Approved HIV reverse transcriptase inhibitors in the past decade. (PubMed, Acta Pharm Sin B) - "Here, we provide a comprehensive review of RT inhibitors (tenofovir alafenamide, rilpivirine, doravirine, dapivirine, azvudine and elsulfavirine) approved in the past decade, regarding their drug discovery, pharmacology, and clinical efficacy in randomized controlled trials. Novel RT inhibitors such as islatravir, MK-8504, MK-8507, MK8583, IQP-0528, and MIV-150 will be also highlighted. Future development may focus on the new generation of novel antiretroviral inhibitors with higher bioavailability, longer elimination half-life, more favorable side-effect profiles, fewer drug-drug interactions, and higher activities against circulating drug-resistant strains."

Journal • Review • Human Immunodeficiency Virus • Immunology • Infectious Disease

Dose Ranging, Switch Study of Islatravir (ISL) and MK-8507 Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013] (clinicaltrials.gov) - P2b | N=161 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Jun 2024 ➔ Jun 2023

Trial completion date • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4

Dose Ranging, Switch Study of Islatravir (ISL) and MK-8507 Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013] (clinicaltrials.gov) - P2b | N=161 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial primary completion date: Jun 2022 ➔ Jun 2023

Trial primary completion date • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4

MK-8507 in Participants With Mild or Moderate Hepatic Impairment (MK-8507-014) (clinicaltrials.gov) - P1 | N=22 | Not yet recruiting | Sponsor: Merck Sharp & Dohme Corp. | Trial completion date: May 2022 ➔ Jan 2023 | Initiation date: Nov 2021 ➔ Jul 2022 | Trial primary completion date: May 2022 ➔ Jan 2023

Trial completion date • Trial initiation date • Trial primary completion date • Hepatitis C • Hepatology • Liver Failure

MK-8507 in Participants With Mild or Moderate Hepatic Impairment (MK-8507-014) (clinicaltrials.gov) - P1; N=22; Not yet recruiting; Sponsor: Merck Sharp & Dohme Corp.

Clinical • New P1 trial • Hepatitis C • Hepatology • Liver Failure

Single oral doses of MK-8507, a novel non-nucleoside reverse transcriptase inhibitor, suppress HIV-1 RNA for a week. (PubMed, J Acquir Immune Defic Syndr) - "The robust antiviral activity, PK, and tolerability of MK-8507 support its continued development as part of a complete once-weekly oral regimen for HIV-1 treatment; combination therapy could mitigate the emergence of resistance-associated variants."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Pharmacokinetic and Safety Profile of the Novel HIV Non-Nucleoside Reverse Transcriptase Inhibitor MK-8507 in Adults without HIV. (PubMed, Antimicrob Agents Chemother) - "Two randomized, double-blind, placebo-controlled phase 1 studies in adults without HIV-1 evaluated the safety, tolerability, and pharmacokinetics of single and multiple doses of MK-8507; drug interaction with midazolam (a cytochrome P450 3A4 substrate) and food effect were also assessed. While 1 pill once a day meets the needs of many PLWH, for others daily administration poses challenges, including treatment fatigue and daily reminders and/or stigma associated with ART (10, 11). While treatment regimens that can be taken less often than daily are attractive to many PLWH, the long-acting injectable combination of cabotegravir/rilpivirine is currently the only treatment option available without daily dosing; however, administration requires injection by a health care professional (12), potentially posing other challenges."

Clinical • Journal • PK/PD data • Fatigue • Human Immunodeficiency Virus • Infectious Disease

Fluoride Pharmacokinetics in Urine and Plasma Following Multiple Doses of MK-8507, an Investigational, Oral, Once-Weekly Non-Nucleoside Reverse Transcriptase Inhibitor. (PubMed, J Clin Pharmacol) - "However, daily urinary fluoride excretion exceeded the threshold following administration of 800 mg MK-8507 (75.1 ?mol [90% CI: 67.5, 82.7]). Assuming a linear relationship between MK-8507 dose and estimated mean daily fluoride released at steady-state, data interpolation suggests that the US EPA reference dose for fluoride would not be exceeded in most patients when administering MK-8507 at doses currently under clinical investigation (?400 mg once-weekly)."

Journal • PK/PD data • Human Immunodeficiency Virus • Immunology • Infectious Disease

[VIRTUAL] No pharmacokinetic interaction between novel NNRTI MK-8507 and Islatravir (IAS-HIV 2021) - "There was no clinically meaningful interaction between MK-8507 and ISL, supporting further clinical development of this 2-drug, once weekly regimen."

PK/PD data • Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] NNRTI MK-8507 does not alter the pharmacokinetics of the combined oral contraceptive levonorgestrel/ethinyl estradiol (IAS-HIV 2021) - "The results of this study support use of hormonal contraceptives in people living with HIV receiving MK-8507."

PK/PD data • Human Immunodeficiency Virus • Infectious Disease

Dose Ranging, Switch Study of Islatravir (ISL) and MK-8507 Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013] (clinicaltrials.gov) - P2b; N=140; Active, not recruiting; Sponsor: Merck Sharp & Dohme Corp.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4 • PCR

[VIRTUAL] RESISTANCE PROFILE OF MK-8507, A NOVEL NNRTI SUITABLE FOR WEEKLY ORAL HIV TREATMENT (CROI 2021) - "It displayed additive antiviral activity and was not antagonistic in combination with all antiretrovirals tested, including islatravir... MK-8507 is a novel and potent NNRTI with activity against common NNRTI resistance-associated variants and has antiviral activity and a resistance profile similar to doravirine and distinct from efavirenz. This in vitro profile supports further development of MK-8507 as a component of a once weekly regimen."

Human Immunodeficiency Virus • Infectious Disease

Dose Ranging, Switch Study of Islatravir (ISL) and MK-8507 Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013] (clinicaltrials.gov) - P2b; N=140; Recruiting; Sponsor: Merck Sharp & Dohme Corp.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD4 • PCR

[VIRTUAL] MODEL-INFORMED DOSE SELECTION FOR ISLATRAVIR/MK-8507 ORAL ONCE-WEEKLY PHASE 2B STUDY (CROI 2021) - P2b | "A real-world adherence model developed based on a claims database of PLWH receiving Abacavir/Dolutegravir/ Lamivudine QD was applied... This analysis supports selection of ISL 20 mg in combination with MK-8507 100 mg, 200 mg or 400 mg for further development as a QW regimen."

P2b data • Human Immunodeficiency Virus • Infectious Disease

"❓Islatravir & MK-8507 once-weekly regimen. What doses should we use in clinical trials ? ➡️ Simulations and Viral dynamics modeling 👍 ISL 20 mg & MK-8507 100 mg, 200 mg and 400 mg #vCROI2021 #CROI2021" (@sebpoule)

Clinical